Indolylalkylamino-methylidenecarbamate derivatives useful as GnRH antagonists

ABSTRACT

The invention relates to a group of novel indole compounds of Formula (I): wherein: R 1 , R 2 , R 4 , R 6 , R 6a , R 7 , R 8 , R 9 , R 10 , and A are as defined in the specification, which are useful as gonadotrophin releasing hormone antagonists. The invention also relates to pharmaceutical formulations of said compounds, methods of treatment using said compounds and to processes for the preparation of said compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a US National Stage under 35 U.S.C § 371 ofInternational Application No. PCT/GB2003/003606, filed Aug. 18, 2003,which claims priority under 35 U.S.C. § 119(a)-(d) to United KingdomPatent Application No. 0219472.8 filed on Aug. 21, 2002, thespecification of which is incorporated by reference herein.

The present invention relates to compounds which are antagonists ofgonadotropin releasing hormone (GnRH) activity. The invention alsorelates to pharmaceutical formulations, the use of a compound of thepresent invention in the manufacture of a medicament, a method oftherapeutic treatment using such a compound and processes for producingthe compounds.

Gonadotropin releasing hormone (GnRH) is a decapeptide that is secretedby the hypothalamus into the hypophyseal portal circulation in responseto neural and/or chemical stimuli, causing the biosynthesis and releaseof luteinizing hormone (LH) and follicle-stimulating hormone (FSH) bythe pituitary. GnRH is also known by other names, includinggonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSHRH and LH/FSH releasing factor (LH/FSH RF).

GnRH plays an important role in regulating the action of LH and FSH (byregulation of their levels), and thus has a role in regulating thelevels of gonadal steroids in both sexes, including the sex hormonesprogesterone, oestrogens and androgens. More discussion of GnRH can befound in WO 98/5519 and WO 97/14697, the disclosures of which areincorporated herein by reference.

It is believed that several diseases would benefit from the regulationof GnRH activity, in particular by antagonizing such activity. Theseinclude sex hormone related conditions such as sex hormone dependentcancer, benign prostatic hypertrophy and myoma of the uterus. Examplesof sex hormone dependent cancers are prostatic cancer, uterine cancer,breast cancer and pituitary gonadotrophe adenoma.

The following disclose compounds purported to act as GnRH antagonists:WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 55116, WO98/55119, WO 98/55123, WO 98/55470, WO 98/55479, WO 99/21553, WO99/21557, WO 99/41251, WO 99/41252, WO 00/04013, WO 00/69433, WO99/51231, WO 99/51232, WO 99/51233, WO 99/51234, WO 99/51595, WO99/51596, WO 00/53178, WO 00/53180, WO 00/53179, WO 00/53181, WO00/53185, WO 00/53602, WO 02/066477, WO 02/066478, WO 02/06645 and WO02/092565.

It would be desirable to provide further compounds, such compounds beingGnRH antagonists. Thus, according to the first aspect of the inventionthere is provided a compound of Formula (I),

wherein

-   -   A represents a direct bond or optionally substituted        C₁₋₅alkylene;    -   R¹ represents hydrogen; optionally substituted C₁₋₈alkyl; or        (CH₂)_(b)—R^(a), wherein R^(a) represents C₃₋₈cycloalkyl and b        is zero or an integer from 1 to 6;    -   R² represents an optionally substituted mono- or bi-cyclic        aromatic ring structure wherein the optional substituents are        selected from cyano, NR³R^(3a), optionally substituted        C₁₋₈alkyl, optionally substituted C₁₋₈alkoxy or halo;    -   R³ and R^(3a) are independently selected from hydrogen;        optionally substituted C₁₋₈alkyl and optionally substituted        aryl;    -   R⁴ is selected from optionally substituted C₁₋₆alkoxy, an        optionally substituted 3- to 8-membered heterocyclic ring        containing from 1 to 4 heteroatoms independently selected from        O, N and S; or a group of formula III-a; III-b; III-c; III-d;        III-e; III-f, III-g, III-h, III-i, III-j or III-k;

-   -   -   wherein het represents an optionally substituted 3- to            8-membered heterocyclic ring containing from 1 to 4            heteroatoms independently selected from O, N and S;

    -   R⁶ and R^(6a), are selected from:        -   (i) R⁶ and R^(6a) are independently selected from hydrogen            and optionally substituted C₁₋₈alkyl; or        -   (ii) R⁶ and R^(6a) together represent carbonyl; or        -   (iii)

-   -   -    represents an optionally substituted 3- to 8-membered            heterocyclic ring containing from 1 to 3 further heteroatoms            independently selected from O, N and S, and R^(6a)            represents hydrogen and optionally substituted C₁₋₈alkyl;

    -   R⁷ represents hydrogen or optionally substituted C₁₋₈alkyl;

    -   R⁸ are selected from: C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and        heterocyclyl wherein R⁸ is optionally substituted with halo,        hydroxy, amino, NO₂, cyano, C₁₋₄alkanoyloxy, N—C₁₋₄alkylamino,        N,N-di-C₁₋₄alkylamino, HO—C₂₋₄alkyl-NH—,        HO—C₂₋₄alkyl-N(C₁₋₄alkyl)—, —S(O_(n))—C₁₋₄alkyl,        —N(R)S(O_(n))—C₁₋₄ alkyl, —S(O_(n))N(R)—C₁₋₄alkyl or        heterocyclyl optionally substituted by C₁₋₄alkyl, C₂₋₄alkenyl or        C₂₋₄alkynyl, wherein R is hydrogen or C₁₋₄alkyl;

    -   R⁹ is selected from:        -   (i) R⁹ represents hydrogen, aryl, a 3- to 10 membered            heterocyclic ring or optionally-substituted C₁₋₈alkyl; and        -   (ii) the structure N(R⁹R¹⁰) represents an            optionally-substituted 3- to 10 membered heterocyclic ring            optionally containing from 1 to 3 further heteroatoms            independently selected from O, N and S;

    -   R¹⁰ meets the definition in option (ii) for R⁹ above or when R⁹        meets the definition in option (i) above R¹⁰ represents hydrogen        or optionally substituted C₁₋₈alkyl;

    -   R¹² and R^(12a) are selected from:        -   (i) R¹² and R^(12a) are independently selected from hydrogen            or optionally substituted C₁₋₈alkyl; or        -   (ii) R¹² and R^(12a) together with the carbon to which they            are attached form an optionally substituted 3 to 7-membered            cycloalkyl ring;

    -   R¹³ and R¹⁴ are selected from:        -   (i) R¹³ is selected from hydrogen; optionally substituted            C₁₋₈alkyl; optionally substituted aryl; —R^(d)—Ar, where            R^(d) represents C₁₋₈alkylene and Ar represents optionally            substituted aryl; and optionally substituted 3- to 8-            membered heterocyclic ring optionally containing from 1 to 3            further heteroatoms independently selected from O, N and S;            and R¹⁴ is selected from hydrogen; optionally substituted            C₁₋₈alkyl and optionally substituted aryl;        -   (ii) wherein R⁴ represents a group of formula III-a, III-b            or III-i, then the group NR¹³(—R¹⁴ ) represents an            optionally substituted 3- to 8- membered heterocyclic ring            optionally containing from 1 to 3 further heteroatoms            independently selected from O, N and S; or        -   (iii) wherein R⁴ represents structure III-e,

-   -   -    represents an optionally substituted 3- to 8- membered            heterocyclic ring optionally containing from 1 to 4            heteroatoms independently selected from O, N and S;        -   n is 0 to 2;            or a salt, pro-drug or solvate thereof.

According to a further feature of the first aspect of the inventionthere is provided a pharmaceutical formulation comprising a compound ofFormula (I), or salt, pro-drug or solvate thereof, and apharmaceutically acceptable diluent or carrier.

According to a further feature of the first aspect of the inventionthere is provided the following uses of a compound of a compound ofFormula (I), or salt, pro-drug or solvate thereof:

-   (a) the use in the manufacture of a medicament for antagonizing    gonadotropin releasing hormone activity;-   (b) the use in the manufacture of a medicament for administration to    a patient, for reducing the secretion of luteinizing hormone by the    pituitary gland of the patient; and-   (c) the use in the manufacture of a medicament for administration to    a patient, for therapeutically treating and/or preventing a sex    hormone related condition in the patient, preferably a sex hormone    related condition selected from prostate cancer and pre-menopausal    breast cancer.

According to a further aspect of the invention there is provided amethod of antagonizing gonadotropin releasing hormone activity in apatient, comprising administering a compound of Formula (I), or salt,pro-drug or solvate thereof, to a patient.

Whilst pharmaceutically-acceptable salts of compounds of the inventionare preferred, other non-pharmaceutically-acceptable salts of compoundsof the invention may also be useful, for example in the preparation ofpharmaceutically-acceptable salts of compounds of the invention.

Whilst the invention comprises compounds of the invention, and salts,pro-drugs or solvates thereof, in a further embodiment of the invention,the invention comprises compounds of the invention and salts thereof.

In the present specification, unless otherwise indicated, an alkyl,alkylene or alkenyl moiety may be linear or branched.

The term “alkylene” refers to the group —CH₂—. Thus, C₈ alkylene forexample is —(CH₂)₈—.

The term “aryl” refers to phenyl or naphthyl.

The term “carbamoyl” refers to the group —CONH₂.

The term “halo” refers to fluoro, chloro, bromo or iodo.

The term “heterocyclyl” or “heterocyclic ring” refers to a 5-10 memberedaromatic mono or bicyclic ring or a 5-10 membered saturated or partiallysaturated mono or bicyclic ring, said aromatic, saturated or partiallyunsaturated rings containing up to 5 heteroatoms independently selectedfrom nitrogen, oxygen or sulphur, linked via ring carbon atoms or ringnitrogen atoms where a bond from a nitrogen is allowed, for example nobond is possible to the nitrogen of a pyridine ring, but a bond ispossible through the 1-nitrogen of a pyrazole ring. Examples of 5- or6-membered aromatic heterocyclic rings include pyrrolyl, furanyl,imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl,isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl andthienyl. A 9 or 10 membered bicyclic aromatic heterocyclic ring is anaromatic bicyclic ring system comprising a 6-membered ring fused toeither a 5 membered ring or another 6 membered ring. Examples of 5/6 and6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl,benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl,quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl,cinnolinyl and naphthyridinyl. Examples of saturated or partiallysaturated heterocyclic rings include pyrrolinyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl anddihydropyrimidinyl. This definition further comprises sulphur-containingrings wherein the sulphur atom has been oxidised to an S(O) or S(O2)group.

The term “aromatic ring” refers to a 5-10 membered aromatic mono orbicyclic ring optionally containing up to 5 heteroatoms independentlyselected from nitrogen, oxygen or sulphur. Examples of such “aromaticrings” include: phenyl, pyrrolyl, furanyl, imidazolyl, triazolyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl,1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. Preferredaromatic rings include 'phenyl, thienyl and pyridyl.

The symbol

denotes where the respective group is linked to the remainder of themolecule.

For the avoidance of doubt, when

together form an optionally substituted 3- to 8- membered heterocyclicring containing from 1 to 3 further heteroatoms independently selectedfrom O, N and S, then the groups shown cyclise to form anitrogen-containing heterocyclic ring, i.e

optionally containing from 1 to 3 further heteroatoms independentlyselected from O, N and S.

Examples of C₁₋₈alkyl include: methyl, ethyl, propyl, isopropyl, butyl,iso-butyl, tert-butyl and 2-methyl-pentyl; example of C₁₋₈alkyleneinclude: methylene, ethylene and 2-methyl-propylene; examples ofC₁₋₈alkoxy include methoxy, ethoxy and butyloxy; examples ofC₁₋₄alkanoyloxy include formyloxy, propanoyloxy and butanoyloxy,examples of N—C₁₋₄alkylamino include N-methylamino and N-ethylamino;examples of N,N-di-C₁₋₄alkylamino, examples of HO—C₂₋₄alkyl-NH includehydroxymethylamino hydroxyethylamino and hydroxypropyamino, examples ofHO—C₂₋₄alkyl-N(C₁₋₄alkyl) include N-methyl-hydroxymethylamino,N-ethyl-hydroxyethylamino, and N-propyl-hydroxypropyamino.

It is to be understood that, insofar as certain of the compounds of theinvention may exist in optically active or racemic forms by virtue ofone or more asymmetric carbon atoms, the invention includes in itsdefinition any such optically active or racemic form which possesses theproperty of antagonizing gonadotropin releasing hormone (GnRH) activity.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, activity of these compounds may be evaluatedusing the standard laboratory techniques referred to hereinafter.

The invention also relates to any and all tautomeric forms of thecompounds of the different features of the invention that possess theproperty of antagonizing gonadotropin releasing hormone (GnRH) activity.

It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It is to be understood that the present inventionencompasses all such solvated forms which possess the property ofantagonizing gonadotropin releasing hormone (GnRH) activity.

Preferred compounds of Formula (I) are those wherein any one of thefollowing or a combination of the following apply.

Preferably A represents optionally substituted C₁₋₅alkylene. Furtherpreferably C₁₋₄alkylene. Most preferably methylene or ethylene.

Preferably R¹ represents hydrogen or optionally substituted C₁₋₆alkyl.More preferably R¹ represents hydrogen, methyl, ethyl or tert-butyl.Most preferably R¹ represents hydrogen.

Preferably R² represents an optionally substituted monocyclic aromaticring structure wherein the optional substituents are selected fromcyano, NR^(e)R^(f), optionally substituted C₁₋₈alkyl (preferably,C₁₋₄alkyl, eg, methyl or ethyl), optionally substituted C₁₋₈alkoxy(preferably, C₁₋₆alkoxy, eg, methoxy, ethoxy or tert-butoxy) or halo(eg, F, Br or Cl) wherein R^(e) and R^(f) are independently selectedfrom hydrogen, C₁₋₆alkyl or aryl. Further preferably R² is optionallysubstituted phenyl wherein the optional substituents are selected fromcyano, NR^(e)R^(f), optionally substituted C₁₋₄alkyl, optionallysubstituted C₁₋₆alkoxy, F, Br or Cl wherein R^(e) and R^(f) are asdefined above. Yet further preferably R² is optionally substitutedphenyl wherein the optional substituents are selected from methyl,ethyl, methoxy, ethoxy, tert-butoxy, F or Cl. Most preferably R²represents

wherein Me represents methyl. Preferably R² bears 1, 2 or 3substituents.

Preferably R³ and R^(3a) are independently selected from hydrogen;optionally substituted C₁₋₆alkyl and, optionally substituted aryl.Further preferably R³ and R^(3a) are independently selected from methyl,ethyl, tert-butyl and phenyl.

Preferably R⁴ is selected from a group of formula III-a, III-g, III-h,III-i, III-j or III-k:

Further preferably R⁴ is selected from one of the following groups:

Yet further preferably R⁴ is selected from one of the following groups:

wherein Me represents methyl.Most preferably R⁴ is selected from one of the following groups:

In one embodiment, R⁶ and R^(6a) each represent hydrogen and Arepresents C₁₋₄alkylene (preferably methylene).

In a further embodiment of the invention R⁶ represents hydrogen, R^(6a)represents methyl, and A represents C₁₋₄alkylene (preferably methylene).

Preferably R⁷ is selected from hydrogen or optionally-substitutedC₁₋₆alkyl. Further preferably R⁷ represents hydrogen, methyl, ethyl ortert-butyl.

Preferably R⁸ is selected from: C₁₋₄alkyl optionally substituted byheterocyclyl, C₁₋₄alkanoyloxyC₁₋₄alkyl or C₁₋₄alkanoyloxy, whereinheterocyclyl is optionally substituted by C₁₋₄alkyl. PreferablyC₁₋₄alkyl or C₁₋₄alkyl substituted by heterocyclyl wherein heterocyclylis optionally substituted by methyl or C₁₋₄alkanoylamino. Mostpreferably ethyl, isopropyl, n-butyl,5-methyl-2-oxo-1,3-dioxol-4-ylmethyl or1-oxoethoxy-(1,1,-dimethyl-ethyl).

Preferably R⁹ comprise part of the heterocyclic ring formed by N(R⁹R¹⁰)or is hydrogen, optionally substituted aryl, an optionally substituted3- to 10 membered heterocyclic ring or optionally substituted C₁₋₄alkylwherein the optional substituents on C₁₋₄alkyl, aryl or a heterocyclicring are selected from: hydroxy, amino, nitro, cyano,optionally-substituted aryl, optionally substituted 3- to 8- memberedheterocyclyl containing from 1 to 4 heteroatoms independently selectedfrom O, N and S, —O—R^(b), C(O)NR^(b)R^(c), —NR^(b)R^(c),—NR^(c)C(O)—R^(b), —C(O)NR^(b)R^(c), —NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b),wherein R^(b) and R^(c) are as defined above.

When R⁹ is a C₁₋₆alkyl group substituted by an optionally-substituted 3to 10 membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from O, N and S, the heterocyclic ring ispreferably selected from pyridyl, thienyl, piperidinyl, imidazolyl,triazolyl, thiazolyl, pyrrolidinyl, piperazinyl, morpholinyl,imidazolinyl, benztriazolyl, benzimidazolyl, pyrimidinyl, pyrazinyl,pyridazinyl, oxazolyl, furanyl, pyrrolyl, 1,3-dioxolanyl, 2-azetinyl,each of which is optionally substituted. Further preferably a group offormula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j orVI-k:, wherein each group is optionally substituted by one or moregroups selected from R¹⁶ on ring carbon atoms or ring heteroatoms wherechemically feasible

Most preferably a group of formula VI-b, VI-i or VI-j:

wherein

-   R¹⁶ represents hydrogen, aryl, a 3- to 10 membered heterocyclic ring    or optionally substituted C₁₋₄alkyl wherein the optional    substituents are selected from: hydroxy, amino, nitro, cyano,    optionally-substituted phenyl, optionally substituted 3- to 8-    membered heterocyclyl containing from 1 to 4 heteroatoms    independently selected from O, N and S, —O—R^(b), C(O)NR^(b)R^(c),    —NR^(b)R^(c), —NR^(c)C(O)—R^(b), —C(O)NR^(b)R^(c),    —NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b), wherein R^(b) and R^(c) are as    defined above;

In a further embodiment of the invention R⁹ is C₁₋₄alkyl optionallysubstituted by cyano, preferably cyanopropyl.

Preferably R¹⁰ comprises part of the heterocyclic ring formed byN(R⁹R¹⁰) or R¹⁰ is hydrogen or optionally substituted C₁₋₆alkyl. Furtherpreferably R¹⁰ comprises part of the heterocyclic ring formed byN(R⁹R¹⁰) or R¹⁰ is selected from: hydrogen, methyl, ethyl or iso-propyl.Most preferably R¹⁰ is hydrogen or comprises part of the heterocyclicring formed by N(R⁹R¹⁰).

When N(R⁹R¹⁰) represent an optionally substituted 3- to 10- memberedheterocyclic ring, N(R⁹R¹⁰) is preferably selected from a 5- or6-membered monocyclic ring containing between 1 and 3 (preferably 1 or2) heteroatom independently selected from O, N and S. Further preferablya 5- or 6-membered monocyclic ring containing between 1 and 3(preferably 1 or 2) heteroatom independently selected from O, N and Sselected from pyrrolidinyl, thienyl, pyrazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl piperazinyl, imidazole, azetidinyl orazetinyl. Further preferably the structure N(R⁹R¹⁰) is a heterocyclicring selected from an optionally-substituted group of formula, IV-a,IV-b, IV-c, IV-d and IV-e, wherein the optional substituents arepreferably selected from the groups listed for R¹⁵ below

Further preferably the structure N(R⁹R¹⁰) is selected from a group offormula Va, Vb, Vc or Vd:

Most preferably the structure N(R⁹R¹⁰) is a group of formula V-c:R¹⁵ represents hydrogen, optionally substituted aryl, an optionallysubstituted 3- to 10 membered heterocyclic ring or optionallysubstituted C₁₋₄alkyl wherein the optional substituents on aryl, aheterocyclic ring or C₁₋₆alkyl are selected from: hydroxy, amino, nitro,cyano, optionally-substituted aryl, optionally substituted 3- to 8-membered heterocyclyl containing from 1 to 4 heteroatoms independentlyselected from O, N and S, —O—R^(b), C(O)NR^(b)R^(c), —NR^(b)R^(c),—NR^(c)C(O)—R^(b), —C(O)NR^(b)R^(c), —NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b),wherein R^(b) and R^(c) are as defined above. Preferably R¹⁵ isheterocyclyl. Further preferably R¹⁵ is selected from: pyridyl,pyrazinyl, pyridazinyl, pyrimidinyl or thiazolyl. Most preferably R¹⁵ ispyridyl.

In a further embodiment of the invention R¹⁵ is selected from pyridyl orC₁₋₄alkyl.

Further preferably pyridyl or methyl.

In a further embodiment of the invention N(R⁹R¹⁰) represent anoptionally substituted 3- to 10- membered heterocyclic ring, wherein theoptional substituents are selected from R¹⁵ as defined above.

Preferably R¹² and R^(12a) are independently selected from: hydrogen,optionally substituted C₁₋₆alkyl or R¹² and R^(12a) together with carbonto which they are attached from an optionally substituted 3- to6-membered cycloalkyl ring. Further preferably R¹² and R^(12a) areindependently selected from: hydrogen, methyl, ethyl or tert-butyl. Mostpreferably R¹² and R^(12a) are both methyl.

Preferably R¹³ and R¹⁴, are independently selected from hydrogen,optionally substituted C₁₋₆alkyl, optionally substituted phenyl and—R^(d)-phenyl, where R^(d) represents C₁₋₆alkylene or and an optionallysubstituted 3- to 8- membered heterocyclic ring (preferably, a 5- or6-membered monocyclic ring) containing from 1 to 3 (preferably 1 or 2)further heteroatoms independently selected from O, N and S. Furtherpreferably R¹³ and R¹⁴, are independently selected from hydrogen orC₁₋₆alkyl.

Where optional substitution is mentioned at various places, this refersto one, two, three or more optional substituents. Unless otherwiseindicated above (ie, where a list of optional substituents is provided),each substituent can be independently selected from C₁₋₈alkyl (eg,C₂₋₆alkyl, and most preferably methyl, ethyl or tert-butyl);C₃₋₈cycloalkoxy, preferably cyclopropoxy, cyclobutoxy or cyclopentoxy;C₁₋₆alkoxy, preferably methoxy or C₂₋₄alkoxy; halo, preferably Cl or F;Hal₃C—, Hal₂CH—, HalCH₂—, Hal₃CO—, Hal₂CHO or Hal CH₂O, wherein Halrepresents halo (preferably F); R^(g)CH₂O—, R^(h)C(O)N(R)—,R^(h)SO₂N(R)— or R^(g)—R^(h)N—, wherein R^(g) and R^(h) independentlyrepresent hydrogen or C₁₋₈alkyl (preferably methyl or C₂₋₆ alkyl orC₂₋₄alkyl), or R^(g)—R^(h)N— represents an optionally substituted C₃₋₈,preferably C₃₋₆, heterocyclic ring optionally containing from 1 to 3further heteroatoms independently selected from O, N and S; hydrogen; orR^(k)C(O)O— or R^(k)C(O)—, R^(k) representing hydrogen, optionallysubstituted phenyl or C₁₋₆alkyl (preferably methyl, ethyl, iso-propyl ortert-butyl). For optional substitution of the heterocyclic ringrepresented by R^(g)—R^(h)N—, at least one (eg, one, two or three)substituents may be provided independently selected from C₁₋₆alkyl (eg,C₂₋₄alkyl, more preferably methyl); phenyl; CF₃O—; F₂CHO—; C₁₋₈alkoxy,preferably methoxy, ethoxy or C₃₋₆alkoxy; C₁₋₈alkoxyC(O), preferablymethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or C₃₋₆alkoxyC(O)—;phenoxycarbonyl; phenoxy; C₁₋₈alkanoyl, preferably acetyl, ethanoyl orC₃₋₆alkyanoyl; carboxy; C₁₋₈alkylS(O)_(nn) wherein nn is an integerbetween 0 and 2, preferably methylthio, ethylthio, C₃₋₆alkylthio,methylsulphinyl, ethylsulphinyl, C₃₋₆alkylsulphinyl, methylsulphonyl,ethylsulphonyl or C₃₋₆alkylsulphonyl; hydroxy; halo (eg, F, Cl or Br);R^(m)R^(n)N— where R^(m) and R^(n) are independently hydrogen orC₁₋₆alkyl (preferably C₂₋₄alkyl, more preferably methyl, most preferablyR^(m)═R^(n)=methyl); and nitro.

Where optional substitution of a ring is mentioned at various places,this most preferably refers to one, two, three or more substituentsselected from C₁₋₈alkyl (eg, C₂₋₆alkyl, and most preferably methyl);C₁₋₈alkoxy, preferably methoxy, ethoxy or C₃₋₆alkoxy; C₁₋₈alkylS(O)_(nn)wherein nn is an integer between 0 and 2, preferably methylthio,ethylthio, C₃₋₆alkylthio, methylsulphinyl, ethylsulphinyl,C₃₋₆alkylsulphinyl, methylsulphonyl, ethylsulphonyl orC₃₋₆alkylsulphonyl; halo (eg, F, Cl or Br); cyano; and NO₂. A preferredgroup of compounds of the invention comprise compounds of Formula (I)wherein:

-   -   N(R⁹R¹⁰) represents an optionally-substituted 3- to 8- membered        heterocyclic ring optionally containing from 1 to 3 further        heteroatoms independently selected from O, N and S, preferably        substituted by heterocyclyl;        or a salt, pro-drug or solvate thereof.        A preferred group of compounds of the invention comprise        compounds of Formula (I) wherein:    -   R⁹ is a C₁₋₆alkyl group substituted by an optionally-substituted        3 to 8 membered heterocyclic ring containing from 1 to 4        heteroatoms independently selected from O, N and S; and    -   R¹⁰ represents hydrogen or C₁₋₆alkyl        or a salt, pro-drug or solvate thereof.

A preferred group of compounds of the invention comprises a compound ofFormula (Ia):

wherein:A, X, R¹, R², R³, R^(3a), R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹² and R^(12a)are as defined above;or a salt, pro-drug or solvate thereof.

A preferred group of compounds of the invention comprises a compound ofFormula (Ib):

wherein:R⁴ is selected from one of the following groups:

and A, X, R¹, R³, R^(3a), R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹², R^(12a),R¹³, and R¹⁴ are as defined above; or a salt, pro drug or solvatethereof.

A further preferred group of compounds of the invention comprises acompound of Formula (Ic):

wherein:R⁴ is selected from one of the following groups:

and A, X, R¹, R², R³, R^(3a), R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹², R^(12a),R¹³, and R¹⁴ are as defined above;or a salt, pro-drug or solvate thereof.

A yet further preferred group of compounds of the invention comprises acompound of Formula (Ia), (Ib) or (Ic) wherein:

R⁴ is a group of Formula IIIa:

NR¹³(—R¹⁴) represents an optionally substituted 7- to 8- memberedbicyclic heterocyclic ring and A, X, R¹, R², R³, R^(3a), R⁴, R⁶, R^(6a),R⁷, R⁸, R⁹, R¹⁰, R¹² and R^(12a) are as defined above; or a salt,pro-drug or solvate thereof.

Particularly preferred compounds according to the present invention arewherein the compound is selected from:

-   isopropyl    [(1E)-({(2S)-2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]carbamate;-   isopropyl    [(1E)-({(2S)-2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]carbamate;    and-   2-[({[(1E)-({(2S)-2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]amino}carbonyl)oxy]-2-methylpropyl    acetate

or a salt, pro-drug or solvate thereof.

According to a further feature of the first aspect of the inventionthere is provided a pharmaceutical formulation comprising a compound ofFormula (Ia), Formula (Ib), Formula (Ic) or preferred compounds of theinvention, or salt, pro-drug or solvate thereof, and a pharmaceuticallyacceptable diluent or carrier.

According to a further feature of the first aspect of the inventionthere is provided the following uses of a compound of Formula (Ia),Formula (Ib), Formula (Ic) or preferred compounds of the invention, orsalt, prodrug or solvate thereof:

-   (a) the use in the manufacture of a medicament for antagonising    gonadotropin releasing hormone activity;-   (b) the use in the manufacture of a medicament for administration to    a patient, for reducing the secretion of luteinizing hormone by the    pituitary gland of the patient; and-   (c) the use in the manufacture of a medicament for administration to    a patient, for therapeutically treating and/or preventing a sex    hormone related condition in the patient, preferably a sex hormone    related condition selected from prostate cancer and pre-menopausal    breast cancer.

The compounds of Formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the Formula (I). Examples of pro-drugs include in-vivohydrolysable esters of a compound of the Formula (I). Various forms ofpro-drugs are known in the art. For examples of such pro-drugderivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the Formula (I)containing a carboxy or a hydroxy group is, for example, apharmaceutically-acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically-acceptable esters for carboxy include C₁₋₆alkoxymethylesters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters forexample pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters.

An in-vivo hydrolysable ester of a compound of the Formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters (including phosphoramidic cyclic esters) and α-acyloxyalkylethers and related compounds which as a result of the in-vivo hydrolysisof the ester breakdown to give the parent hydroxy group/s. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

The compounds of Formula (I) can be prepared by a process comprising astep selected from (a) to (b) as follows, these processes are providedas a further feature of the invention:—

-   (a) Reaction of a compound of formula XXXII as follows

wherein X is a leaving group;

-   (b) Reaction of a compound of Formula XXXIV as follows

and thereafter if necessary:

-   i) converting a compound of the Formula (I) into another compound of    the Formula (I);-   ii) removing any protecting groups;-   iii) forming a salt, pro-drug or solvate.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of Formula (I) may involve, at an appropriate stage, theaddition and subsequent removal of one or more protecting groups.

The protection and de-protection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thede-protection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or alkoxycarbonyl group or an aroyl group maybe removed for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thede-protection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

EXPERIMENTAL GENERAL REACTION SCHEMES

In the following schemes wherein Ri, Rii and Riii represent optionalsubstituents on the phenyl ring which are optionally protected asnecessary and R represents a protecting group, group R² has beendepicted as substituted phenyl for illustration purposes only. Otherdefinitions of R² are also appropriate.

Tryptamines, such as 3 can be synthesised by the classic Fisher indolesynthesis reaction by the condensation of a hydrazine 1 and a ketone 2,bearing hydrogen atoms (α to the carbonyl (Scheme a). Treatment of thesereactants in a suitable solvent, such as acetic acid, ethanol,tert-butanol, toluene, in the presence of an acid, such as sulphuric,hydrochloric, polyphosphoric and/or a Lewis acid, for example, borontrifluoride, zinc chloride, magnesium bromide, at elevated temperatures(for example 100° C.), gives the desired product. R represents aprotecting group, eg tert-butylcarbamate or phthalimide.

Tryptamines, such as represented in structure 5, can also be made usingaldehydes 4, bearing hydrogen atoms α to the carbonyl, by cyclizationusing the conditions above. In this case the substituent at the2-position must be added later (see scheme d).

Tryptamine may also be synthesised utilising the Granburg reaction,wherein a hyradazine 1 is mixed with ketone 6, bearing a chlorine atom γto the carbonyl, and heated in a suitable solvent such as ethanol,tert-butanol, toluene at a temperature between 50° C. and 120° C.(Scheme c).

The tryptamine 5 can be treated with a ‘bromine source’, such asmolecular bromide, pyridinium tribromide, pyrrolidone hydrobromide orpolymer supported reagent equivalents, in an inert solvent such aschloroform, methylene chloride at −10° C. to 25° C. to yield the 2-bromocompound 8 (Scheme d). Reaction under Suzuki conditions with apalladium(0) catalyst, a weak base such aqueous sodium carbonate orsaturated sodium hydrogen carbonate and the like, and a substituted arylboronic acid from commercial sources or prepared (as described in:Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.,-H Chem. Sci. 1986, 26,311-314), in an inert solvent such as toluene, benzene, dioxane, THF,DMF and the like, with heating between 25° C. and 100° C., preferably80° C., for a period of 1-12 hours, to give the desired compound 3.

The hydrazines 1 can be purchased from commercial sources either as afree base or suitable salt (e.g. hydrochloride), which are bothacceptable under the reaction conditions. Hydrazines may be synthesisedby the two-step process of diazotisation of an aniline, under thepreferred conditions of concentrated hydrochloric acid sodium nitrite ata temperature between −10° C. and −5° C., then reduction under thepreferred conditions of tin(II) chloride in concentrated hydrochloricacid at a temperature between −10° C. and −5° C.

Substituted ketones 2 can be prepared, as outlined in Scheme e startingfrom appropriate acid chlorides such as 9. Treatment of the acidchloride with N,N-dimethylhydroxylamine hydrochloride in the presence ofan amine base such as triethylamine, and a suitable solvent such asmethylene chloride at a temperature of −10° C. to 25° C., yields theamide 10. Further reaction with a substituted aryl organolithium(prepared essentially as described in Wakefield B, J.; OrganolithiumMethods Academic Press Limited, 1988, pp. 27-29 and references therein)in an inert solvent such as tetrahydrofuran, diethyl ether, benzene,toluene or mixture thereof and the like, at a temperature between −100°C. and 0° C. then quenching of the reaction mixture with a mineral acidsuch as hydrochloric acid, yields the aryl ketone 2.

Commencing with a readily available amino acid with a suitable chainlength[a]11, the nitrogen atom can be brought in at the beginning of thesynthesis by the route shown in Scheme f. Protection of the amine groupof 11 with a tert-butylcarbamate group is achieved by condensation withdi-tert-butyl di-carbonate in the presence of an amine base, for exampletriethylamine, in an inert solvent such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran and mixtures thereof andthe like, at a temperature of −10° C. to 25° C. Coupling of the acidproduct with N,N-dimethylhydroxylamine in the presence of a couplingreagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC) or 1,3-dicyclohexylcarbodiimide (DCC) or the like, with or without1-hydroxybenotriazole (HOBt), and suitable amine base, such astriethylamine and the like, in an inert solvent such as methylenechloride, chloroform, dimethylformamide, or mixture thereof, at or nearroom temperature for a period of 3 to 24 hours provided thecorresponding coupled product 12. Following the same route describedabove for scheme d, the aryl group can then be installed.

Scheme g illustrates another method for the synthesis of ketone such as2 and 16, where the nitrogen group is introduced at a latter stage. Asabove a Weinreb amide 14 can be synthesised from an acid chloride.Treatment with the required amine, in an inert solvent such as THF,toluene, water and the such like can displace the group X to give 17. Asabove the aryl group can be introduced by displacement of the Weinrebamide with a suitable aryl lithium nucleophile. Alternatively thenitrogen atom can be introduced already protected as a phthalimide bydisplacement of the group x by potassium phthaliride, or similar saltthereof, by heating in an inert polar solvent such as DMF, DMSO, THF,toluene with or without the presence of a catalyst such astetrabutylammonium iodide and the such like, to yield the compound 15.Again displacement of the Weinreb amide with an organolithium speciescompletes the synthesis of a ketone suitable for cyclization under theFischer condition described above for indole synthesis.

An alternative approach to a phthalimide protected nitrogen ketone, suchas 16, can be taken by firstly treating a lactone, with an organolithiumspecies as in the above schemes in a suitable solvent such as THF orether at a low temperature of between −100° C. and −50° C. to yield aprimary alcohol 18 (Scheme h). The hydroxyl function of 18 is replacedwith a phthalimide group by a Mitsunobu reaction with an activatingagent such as diethylazodicarboxylate (DEAD),diisopropylazodicarboxylate or the like with triphenylphosphine,tri-butylphosphine and the like, in an inert solvent such as benzene,toluene, tetrahydrofuran or mixtures thereof to give the desired ketone16.

An analogous reaction to that described in Scheme h can be used toproduce the respective intermediate required to introduce a β-methylgroup at R⁶ in the final molecule (see Scheme h1).

If the group R¹ was not present on the starting hydrazine beforecyclization to form an indole it may be added post cyclization by analkylation reaction (19→3). The indole is de-protonated by a strongbase, such as sodium hydride, n-butyl lithium, lithium diisopropylamine,sodium hydroxide, potassium tert-butoxide in a suitable inert solventsuch as THF, DMF, DMSO and the such like, and an alkyl halide added andthe mixture stirred at a temperature between 0° C. and room temperature.

Depending on the route used above a tryptamine 20 suitable forconversion to a cyano-guandine can be formed by removal of theprotecting group, for example if a tert-butylcarbamate group was usedthen removal is accomplished using a strong acid, for exampletrifluoroacetic acid or hydrochloric acid in an inert solvent such asmethylene chloride, chloroform, THF or dioxane at a temperature between−20° C. and 25° C. A phthalimide group, for example, can be removed byhydrazine in a suitable solvent for example methanol, ethanol, methylenechloride, chloroform, THF dioxane at a temperature between −20° C. and25° C. The primary amine 20 can be converted to a cyano-guanidine 22 bythe two step process of reaction with diphenyl cyanocarbonimidate in aninert organic solvent such as isoproplyl alcohol, methylene chloride,chloroform, benzene, tetrahydrofuran and the like, at a temperaturebetween −20° C. and 50° C., followed by condensation with anappropriately substituted amine in an inert organic from the list above,with heating at a temperature between −20° C. and 100° C. (Scheme I20→21→22). Further treatment of 22 with 2 molar Hydrochloric acid inmethanol at elevated temperature yields guanidine compounds 23. 23 canthen be reacted with a compound 24 wherein X is a leaving group such asp-nitrophenol, at a temperature of about 0° C. in a suitable solventsuch as DMF to form a compound 25.

Alternatively, an alkyl chloroformate can be reacted with a solution ofpotassium thiocyanate in toluene/acetonitrile at about room temperature.The product of this reaction can then be reacted with tryptamine 20, indichloromethane (DCM) at 0° C. to form 26. 26 can then be converted to27 by reacting with the appropriate primary or secondary amine in thepresence of EDC/DIPEA in dichloromethane at a temperature of about 0° C.

EXAMPLES

The invention will now be illustrated with the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at room temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon ornitrogen;

(iii) yields are given for illustration only and are not necessarily themaximum attainable;

(iv) the structures of the end-products of the Formula (I) wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (1R) or NMR analysis;

(vi) chromatography was performed on silica (Merck Keiselgel: Art.9385);

(vii) isolute™ refers to silica (SiO₂) based columns with irregularparticles with an average size of 50 μm with nominal 60 Å porosity[Source: Jones Chromatography, Ltd., Glamorgan, Wales, United Kingdom].

Abbreviations

-   brine a saturated solution of sodium chloride in distilled water-   DCC 1,3-dicyclohexylcarbodiimide-   DCM dichloromethane-   DEAD diethylazodicarboxylate-   DIPEA di-isopropylethylamine-   DMSO Dimethyl sulphoxide-   DMF dimethylformamide-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   HOBt 1-hydroxybenotriazole-   THF tetrahydrofuran

Example 1Ethyl(1E-({2-[5-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidenecarbamate

To a stirred, cooled (0° C.) solution of 5 (72 mg, 0.13 mmol),4-pyrrolidin-3-yl pyridine (30 mg, 0.20 mmol) andN,N-diisopropylethylamine (46 μl, 0.26 mmol) in DCM (3 ml) was added EDC(52 mg, 0.27 mmol). After stirring for 1 hour at 0° C., the reactionmixture was stirred at ambient temperature for 16 hours. The reactionwas quenched by the addition of sodium bicarbonate (3 ml, sat. aq.) andthe phases were separated. The aqueous phase was extracted with DCM (2×5ml), and the combined organic layers were dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by chromatographyon SiO₂, eluting with a gradient 4-8% MeOH/DCM to give 8 as a yellowfoam (20 mg).

Mass Spectrum m/e 649.3 (M⁺+H).

NMR Spectrum (CDCl3, δ values) 1.28 (t, 3H), 1.47-1.79 (m, 10H), 1.88(m, 1H), 2.19 (m, 1H), 1.35 (s, 6H), 2.76 (m, 2H), 3.13-3.42 (m, 6H),3.44-3.59 (m, 4H), 3.62 (dd, 1H), 4.08 (q, 2H), 6.98 (s, 1H), 7.05 (m,3H), 7.15 (s, 2H), 7.30 (d, 1H), 7.45 (s, 1H), 8.23 (s, 1H), 8.50 (d,2H).

Starting materials were prepared as described in Scheme 1 below.

(1)

n-Butyl chloroformate (2 g, 14.64 mmol) was added to a stirred solutionof potassium thiocyanate (7.83 g, 80.57 mmol) in toluene (25 ml) andacetonitrile (100 ml) at ambient temperature. After stirring for 3 daysthe reaction mixture was filtered through a pad of celite and thefiltrate reduced in vacuo. The residue was triturated withDCM/iso-hexane(1:1), filtered and the filtrate reduced in vacuo. Thecrude product was purified by chromatography on SiO₂, eluting withDCM/iso-hexane(1:4) to give 1 as a yellow liquid (580 mg).

¹H NMR Spectrum (300Mz, CDCl3, δ values) 0.95 (m, 3H), 1.40 (m, 2H),1.68 (m, 2H), 4.21 (t, 2H).

(5)

A solution of 2 (100 mg, 0.25 mmol) in DCM (3 ml) was added to astirred, cooled (0° C.) solution of 1 (29 μl, 0.25 mmol) in DCM (2 ml)under N₂. The cooling bath was removed and stirring was continued for 2hours. The reaction was quenched by the addition of water (3 ml) and thephases were separated. The aqueous phase was extracted with DCM (2×5ml), and the combined organic layers were washed with brine, dried overMgSO₄ and concentrated in vacuo to give 5 as a white solid (144 mg).

Mass Spectrum m/e 535.2 (M⁺+H).

¹H NMR Spectrum (300 MHz, CDCl3, δ values) 1.20-1.36 (m, 3H), 1.48-1.83(m, 10H), 2.40 (s, 6H), 2.80 (m, 2H), 3.28 (t, 2H), 3.55 (m, 2H), 3.95(m, 2H), 4.08-4.24 (m, 2H), 6.99-7.09 (m, 2H), 7.20 (s, 2H), 7.24-7.35(m, 1H), 7.65 (s, 1H), 7.97 (s, 1H), 8.20 (s, 1H), 9.70 (m, 1H).

Examples 1.1-1.2

Following a procedure similar to that described in example 1, thefollowing examples were prepared.

Mass Spectrum m/e NMR Spectrum (M⁺ + H) (CDCl3, δ values) 1.1

661.5 1.25 (m, 6H), 1.54 (m,2H),1.56-1.74 (m, 8H), 1.88 (m,1H), 2.18 (m,1H), 2.35 (s,6H), 2.76 (m, 2H), 3.12-3.40(m, 6H), 3.42-3.58 (m, 4H),3.63(dd, 1H), 4.85 (m, 1H),6.96 (s, 1H), 7.04 (d, 3H), 7.15(s, 2H), 7.30 (d,1H), 7.45 (s,1H), 8.35 (s, 1H), 8.50 (d, 2H). 1.2

675.5 0.93 (t, 3H), 1.20-1.45 (m, 4H),1.46-1.75 (m, 10H), 1.89 (m,1H),2.19 (m, 1H), 2.34 (s,6H), 2.76 (m, 2H), 3.12-3.40(m, 6H), 3.43-3.69 (m,5H),4.02 (m, 2H), 6.98 (s, 1H),7.06 (d, 3H), 7.17 (s, 2H), 7.30(m, 1H),7.46 (s, 1H), 8.40 (s,1H), 8.51 (d, 2H).

Example 2 isopropyl[(1E)-({(2S)-2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]carbamate

To a stirred, cooled (0° C.) solution of 13 (543 mg, 1.06 mmol),4-pyrrolidin-3-yl pyridine (200 mg, 1.35 mmol) andN,N-diisopropylethylamine (188 μl, 1.08 mmol) in DCM (15 ml) was addedEDC (173 mg, 0.90 mmol). After stirring for 16 hours at ambienttemperature in the dark, the reaction mixture was cooled (0° C.) andfurther N,N-diisopropylethylamine (94 μl, 0.54 mmol) and EDC (86 mg,0.45 mmol) were added. The reaction mixture was stirred for 30 min at 0°C. and 4 hours at ambient temperature. The reaction was quenched by theaddition of water (15 ml) and the phases were separated. The aqueousphase was extracted with DCM (2×10 ml), and the combined organic layerswere washed with brine (10 ml, sat. aq.), dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by chromatographyon SiO₂, eluting with a gradient of 5-7% MeOH/DCM to give Example 2 as ayellow foam (266 mg).

Mass Spectrum m/e 715.3 (M⁻−H).

NMR Spectrum (CDCl3, δ values) 1.20-1.39 (m, 10H), 1.40-1.70 (m, 14H),1.72-1.93 (m, 1H), 2.14 (m, 1H), 2.35 (s, 6H), 3.20-3.70 (m, 11H), 4.83(m, 1H), 6.95-7.10 (m, 6H), 7.32 (d, 1H), 7.48 (s, 1H), 8.02 (s, 1H),8.50 (d, 2H).

Starting materials were prepared as described in Scheme 2 below.

(13)

A solution of 11 (412 mg, 0.90 mmol) in DCM (7 ml) was added to astirred, cooled (0° C.) solution of 4 (131 mg, 0.90 mmol) in DCM (8 ml)under N₂. The cooling bath was removed and stirring was continued for 2hours. The reaction was quenched by the addition of water (10 ml) andthe phases were separated. The aqueous phase was extracted with DCM(2×10 ml), and the combined organic layers were washed with brine, driedover MgSO₄ and concentrated in vacuo to give 13 as a yellow solid (573mg).

Mass Spectrum m/e 603.3 (M⁺+H).

NMR Spectrum (CDCl3, δ values) 1.18-1.67 (m, 24H), 2.38 (s, 6H), 3.45(s, 2H), 3.55 (m, 1H), 4.00 (m, 1H), 4.14 (m, 2H), 4.86(m, 1H),7.01-7.10 (m, 2H), 7.14 (s, 2H), 7.32 (d, 1H), 7.56 (s, 1H), 7.73 (s,1H), 7.96(s, 1H), 9.55 (m, 1H).

Example 2.1

Following a procedure similar to that described in Example 2, thefollowing example was prepared.

Mass Spectrum NMR Spectrum m/e (M^(—) H) (CDCl3, δ values) 2.1

701.2 1.00-1.40 (m, 10H), 1.42-1.95(m, 14H), 2.15 (m, 1H), 2.35(s, 6H),3.20-3.80 (m, 9H),4.55-4.90 (m, 2H), 6.99-7.12(m, 5H), 7.15 (d, 1H),7.32(d, 1H), 7.55 (s, 1H), 8.05(s, 1H), 8.50 (d, 2H).

Example 3Isopropyl(1E)-({2-[5-(1,1-dimethyl-2-oxo-2-(N,N-diethylamino)ethyl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidenecarbamate

To a stirred, cooled (0° C.) solution of 19 (584 mg, 1.06 mmol),4-pyrrolidin-3-yl pyridine (236 mg, 1.59 mmol) andN,N-diisopropylethylamine (277 μl, 1.59 mmol) in DCM (15 ml) was addedEDC (204 mg, 1.06 mmol). After stirring for 16 hours at ambienttemperature in the dark, the reaction mixture was cooled (0° C.) andfurther N,N-diisopropylethylamine (185 μl, 1.06 mmol) and EDC (102 mg,0.53 mmol) were added. The reaction mixture was stirred for 30 minutesat 0° C. and 4 hours at ambient temperature. The reaction was quenchedby the addition of water (15 ml) and the phases were separated. Theaqueous phase was extracted with DCM (2×10 ml), and the combined organiclayers were washed with brine (10 ml, sat. aq.), dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by chromatographyon SiO₂, eluting with a gradient of 5-7% MeOH/DCM to give 21 as a paleyellow foam (420 mg).

Mass Spectrum m/e 663.4 (M⁻−H)

NMR Spectrum (CDCl3, δ values) 0.70 (m, 3H), 1.13 (m, 3H), 1.26 (dd,6H), 1.60 (s, 6H), 1.88 (m, 1H), 2.18 (m, 1H), 2.34(s, 6H), 2.92 (m,2H), 3.13-3.44 (m, 8H), 3.50 (m, 2H), 3.63 (dd, 1H), 4.85 (m, 1H), 6.96(s, 1H), 7.04 (d, 3H), 7.16 (s, 2H), 7.30 (d, 1H), 7.41 (s, 1H), 8.30(s, 1H), 8.50 (d, 2H).

Starting materials were prepared as described in Scheme 3 below.

(19)

A solution of 17 (190 mg, 0.47 mmol) in DCM (7 ml) was added to astirred, cooled (0° C.) solution of 4 (68 mg, 0.47 mmol) in DCM (3 ml)under N₂. The cooling bath was removed and stirring was continued for 2hours. The reaction was quenched by the addition of water (10 ml) andthe phases were separated. The aqueous phase was extracted with DCM(2×10 ml), and the combined organic layers were washed with brine, driedover MgSO₄ and concentrated in vacuo to give 19 as a yellow solid (260mg).

Mass Spectrum m/e 551.2 (M⁺+H).

NMR Spectrum (CDCl3, δ values) 0.71 (m, 3H), 1.13 (m, 3H), 1.27 (d, 6H),1.63 (s, 6H), 2.40 (s, 6H), 2.95 (m, 2H), 3.26(t, 2H), 3.36 (m, 2H),3.95 (m, 2H), 4.90 (m, 1H), 7.00-7.06 (m, 2H), 7.20 (s, 2H), 7.30 (d,1H), 7.61 (s, 1H), 7.83 (s, 1H), 8.07 (s, 1H), 9.72 (m, 1H).

Example 3.1

Following a procedure similar to that described in Example 3, thefollowing example was prepared.

Mass Spectrum NMR Spectrum m/e (M^(—)H) (CDCl3, δ values) 3.1

687.3 1.00-1.80 (m, 8H), 1.27 (d,6H), 1.60 (d, 6H), 1.90 (m,1H), 2.20(m, 1H), 2.35 (s,6H), 3.14-3.80 (m, 10H),4.60-4.80 (m, 1H), 4.85 (m,1H),6.99 (s, 1H), 7.05 (d,2H), 7.10-7.19 (m, 3H), 7.30(d, 1H), 7.49 (s, 1H),8.10(s, 1H), 8.54 (d, 2H).

Example 4Isopropyl(1E)-({2-[5-[2-(N,N-diethylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}amino)(4-methylpiperazin-1-yl)methylidenecarbamate

To a stirred, cooled (0° C.) solution of 19 [see Example 3] (217 mg,0.39 mmol), N-methylpiperazine (66 μl, 0.59 mmol) andN,N-diisopropylethylamine (82 μl, 0.47 mmol) in DCM (4 ml) was added EDC(76 mg, 0.40 mmol). After stirring for 16 hours at ambient temperature,the reaction mixture was cooled (0° C.) and furtherN,N-diisopropylethylamine (41 μl, 0.24 mmol) and EDC (38 mg, 0.20 mmol)were added. The reaction mixture was stirred for 30 minutes at 0° C. and4 hours at ambient temperature. The reaction was quenched by theaddition of water (10 ml) and the phases were separated. The aqueousphase was extracted with DCM (2×10 ml), and the combined organic layerswere washed with brine (5 ml, sat. aq.), dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by chromatographyon SiO₂, eluting with a gradient of 2-10% MeOH/DCM to give 23 as a whitesolid (130 mg).

Mass Spectrm m/e 617.5 (M⁺+H).

NMR Spectrum (CDCl3, δ values) 0.74 (m, 3H), 1.15 (m, 3H), 1.28 (d, 6H),1.62 (s, 6H), 2.23 (s, 3H), 2.27 (t, 4H), 2.40 (s, 6H), 2.93 (m, 2H),3.19 (m, 2H), 3.25 (t, 4H), 3.39 (m, 4H), 4.86 (m, 1H), 7.05 (m, 2H),7.15 (s, 2H), 7.32 (d, 1H), 7.43 (s, 1H), 8.05 (s, 1H), 8.19 (m, 1H).

Examples 4.1-4.2

Following a procedure similar to that described in Example 4, thefollowing examples were prepared.

Mass Spectrum m/e NMR Spectrum (M⁺ + H) (CDCl3, δ values) 4.1

627.3 0.72 (m, 3H), 1.14 (s, 3H), 1.27 (d,6H), 1.55-1.70 (m, 8H), 1.78(m, 2H),2.40 (s, 6H), 2.70 (m, 1H), 2.93 (m,2H), 3.02-3.24 (m, 4H), 3.38(m, 6H),4.86 (m, 1H), 7.07 (m, 2H), 7.15 (s,2H), 7.33 (d, 1H), 7.40 (s,1H), 8.14(s, 1H), 8.35 (s, 1H). 4.2

601.8 0.74 (m, 3H), 1.14 (m, 3H), 1.25 (d,6H), 1.49 (m, 2H), 1.60 (s,6H), 2.10(m, 2H), 2.38 (s, 6H), 2.83-3.10 (m,4H), 3.18 (t, 2H), 3.38 (m,2H), 3.54(m, 2H), 4.85 (m, 1H), 7.03 (s, 1H),7.09 (d, 1H), 7.16 (s, 2H),7.35 (d,1H), 7.43 (s, 1H), 8.19 (s, 1H).

Example 5(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl(1E)-({2-[5-[2-(diethylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylidenecarbamate

To a cooled (0° C.), stirred solution of (26) (118 mg, 0.19 mmol) in DMF(3 ml), under N₂, was added NaH (16 mg, 0.40 mmol). After stirring for30 minutes, a solution of 27 (62 mg, 0.21 mmol) in DMF (2 ml) was addeddropwise. The reaction mixture was stirred at 0° C. for 4 hours and leftto stand at −20° C. for 16 hours. The reaction was quenched by theaddition of water (15 ml) and then extracted with EtOAc (3×10 ml). Thecombined organic layers were washed with brine (10 ml sat. aq.), driedover MgSO₄ and concentrated in vacuo. The crude product was purified bychromatography on SiO₂, eluting with a gradient of 2-10% MeOH/DCM togive 28 as a yellow solid (45 mg).

Mass Spectrum m/e 733.3 (M⁻−H).

NMR Spectrum (CDCl3, δ values) 0.73 (m, 3H), 1.14 (m, 3H), 1.60 (s, 6H),1.90 (m, 1H), 2.10 (s, 3H), 2.22 (m, 1H), 2.35 (s, 6H), 2.90 (m, 2H),3.14-3.62 (m, 11H), 4.79 (s, 2H), 6.99 (s, 1H), 7.00-7.12 (m, 3H), 7.17(s, 2H), 7.34 (d, 1H), 7.41 (s, 1H), 8.05 (s, 1H), 8.54 (m, 2H).

Example 62-[({[(1E)-({(2S)-2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]amino}carbonyl)oxy]-2-methylpropylacetate

To a cooled (0° C.), stirred solution of (29) (50 mg, 74.9 μmol) in DMF(2 ml), under N₂, was added NaH (7 mg, 0.16 mmol). After stirring for 30minutes a solution of (30) (67 mg, 0.23 mmol) in DMF (2 ml) was addeddropwise. The reaction mixture was stirred at 0° C. for 40 minutes. Thereaction was quenched by the addition of water (15 ml) and thenextracted with EtOAc (3×10 ml). The combined organic layers were washedwith brine (10 ml sat. aq.), dried over MgSO₄ and concentrated in vacuo.The crude product was purified by chromatography on SiO₂, eluting with agradient of 5-10% MeOH/DCM to give 31 as a yellow solid (10 mg).

Mass Spectrum m/e 789.3 (M⁺+H).

NMR Spectrum (CDCl3, δ values) 1.10-1.70 (m, 24H), 1.75-1.90 (m, 1H),2.00 (s, 3H), 2.15-2.30 (m, 1H), 2.30 (s, 6H), 3.17 (m, 1H), 3.28-4.00(m, 12H), 6.86(s, 2H), 6.95-7.15 (m, 3H), 7.20-7.30 (m, 2H), 7.46 (s,1H), 8.18 (d, 1H), 8.50 (d, 2H).

Therapeutic Uses

Compounds of Formula (I) are provided as medicaments for antagonisinggonadotropin releasing hormone (GnRH) activity in a patient, eg, in menand/or women. To this end, a compound of Formula (I) can be provided aspart of a pharmaceutical formulation which also includes apharmaceutically acceptable diluent or carrier (eg, water). Theformulation may be in the form of tablets, capsules, granules, powders,syrups, emulsions (eg, lipid emulsions), suppositories, ointments,creams, drops, suspensions (eg, aqueous or oily suspensions) orsolutions (eg, aqueous or oily solutions). If desired, the formulationmay include one or more additional substances independently selectedfrom stabilising agents, wetting agents, emulsifying agents, buffers,lactose, sialic acid, magnesium stearate, terra alba, sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butterand ethylene glycol.

The compound is preferably orally administered to a patient, but otherroutes of administration are possible, such as parenteral or rectaladministration. For intravenous, subcutaneous or intramuscularadministration, the patient may receive a daily dose of 0.1 mgkg⁻¹ to 30mgkg⁻¹ (preferably, 5 mgkg⁻¹ to 20 mgkg⁻¹) of the compound, the compoundbeing administered 1 to 4 times per day. The intravenous, subcutaneousand intramuscular dose may be given by means of a bolus injection.Alternatively, the intravenous dose may be given by continuous infusionover a period of time. Alternatively, the patient may receive a dailyoral dose which is approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day. Asuitable pharmaceutical formulation is one suitable for oraladministration in unit dosage form, for example as a tablet or capsule,which contains between 10 mg and 1 g (preferably, 100 mg and 1 g) of thecompound of the invention.

Buffers, pharmaceutically acceptable co-solvents (eg, polyethyleneglycol, propylene glycol, glycerol or EtOH) or complexing agents such ashydroxy-propyl β cyclodextrin may be used to aid formulation.

One aspect of the invention relates to the use of compounds according tothe invention for reducing the secretion of LH and/or FSH by thepituitary gland of a patient. In this respect, the reduction may be byway of a reduction in biosynthesis of the LH and FSH and/or a reductionin the release of LH and FSH by the pituitary gland. Thus, compoundsaccording to the invention can be used for therapeutically treatingand/or preventing a sex hormone related condition in the patient. By“preventing” we mean reducing the patient's risk of contracting thecondition. By “treating” we mean eradicating the condition or reducingits severity in the patient. Examples of sex, hormone related conditionsare: a sex hormone dependent cancer, benign prostatic hypertrophy, myomaof the uterus, endometriosis, polycystic ovarian disease, uterinefibroids, prostatauxe, myoma uteri, hirsutism and precocious puberty.Examples of sex hormone dependent cancers are: prostatic cancer, uterinecancer, breast cancer and pituitary gonadotrophe adenoma.

The compounds of the invention may be used in combination with otherdrugs and therapies used to treat/prevent sex-hormone relatedconditions.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

In the field of medical oncology examples of such combinations includecombinations with the following categories of therapeutic agent:

i) anti-angiogenic agents (for example linomide, inhibitors of integrinαvβ3 function, angiostatin, endostatin, razoxin, thalidomide) andincluding vascular endothelial growth factor (VEGF) receptor tyrosinekinase inhibitors (RTKIs) (for example those described in internationalpatent applications publication nos. WO-97/22596, WO-97/30035,WO-97/32856 and WO-98/13354, the entire disclosure of which documents isincorporated herein by reference);

ii) cytostatic agents such as anti-oestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (forexample megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrozole, vorazole, exemestane), anti-progestogens,anti-androgens (for example flutamide, nilutamide, bicalutamide,cyproterone acetate), inhibitors of testosterone 5α-dihydroreductase(for example finasteride), anti-invasion agents (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function) and inhibitors of growth factorfunction, (such growth factors include for example epidermal growthfactor (EGF), platelet derived growth factor and hepatocyte growthfactor such inhibitors include growth factor antibodies, growth factorreceptor antibodies, tyrosine kinase inhibitors and serine/threoninekinase inhibitors);

iii) biological response modifiers (for example interferon);

iv) antibodies (for example edrecolomab); and

v) anti-proliferative/anti-neoplastic drugs and combinations thereof, asused in medical oncology, such as anti-metabolites (for exampleanti-folates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); anti-tumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);anti-mitotic agents (for example vinca alkaloids like vincristine andtaxoids like taxol, taxotere); enzymes (for example asparaginase);thymidylate synthase inhibitors (for example raltitrexed); topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, irinotecan).

The compounds of the invention may also be used in combination withsurgery or radiotherapy.

Assays

The ability of compounds according to the invention to act asantagonists of GnRH can be determined using the following in vitroassays.

Binding Assay using Rat Pituitary GnRH Receptor

The assay is performed as follows:—

-   1. Incubate crude plasma membranes prepared from rat pituitary    tissues in a Tris.HCl buffer (pH. 7.5, 50 mM) containing bovine    serum albumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and    the test compound. Incubation is at 4° C. for 90 minutes to 2 hours.-   2. Rapidly filter and repeatedly wash through a glass fibre filter.-   3. Determine the radioactivity of membrane bound radio-ligands using    a gamma counter.

From this data, the IC₅₀ of the test compound can be determined as theconcentration of the compound required to inhibit radio-ligand bindingto GnRH receptors by 50%.

Compounds according to the present invention have activity at aconcentration from 1 nM to 5 μM.

Binding Assay using Human GnRH Receptor

Crude membranes prepared from CHO cells expressing human GnRH receptorsare sources for the GnRH receptor. The binding activity of compoundsaccording to the invention can be determined as an IC₅₀ which is thecompound concentration required to inhibit the specific binding of[¹²⁵I]buserelin to GnRH receptors by 50%. [¹²⁵I]Buserelin (a peptideGnRH analogue) is used here as a radiolabelled ligand of the receptor.

Assay to Determine Inhibition of LH Release

The LH release assay can be used to demonstrate antagonist activity ofcompounds, as demonstrated by a reduction in GnRH-induced LH release.

Preparation of Pituitary Glands

Pituitary glands obtained from rats are prepared as follows. Suitablerats are Wistar male rats (150-200 g) which have been maintained at aconstant temperature (eg, 25° C.) on a 12 hour light/12 hour dark cycle.The rats are sacrificed by decapitation before the pituitary glands areaseptically removed to tube containing Hank's Balanced Salt Solution(HBSS). The glands are further processed by:—

-   1. Centrifugation at 250×g for 5 minutes;-   2. Aspiration of the HBSS solution;-   3. Transfer of the glands to a petri dish before mincing with a    scalpel;-   4. Transfer of the minced tissue to a centrifuge tube by suspending    the tissue three successive times in 10 ml aliquots of HBSS    containing 0.2% collagenase and 0.2% hyaluronidase;-   5. Cell dispersion by gentle stirring of the tissue suspension while    the tube is kept in a water bath at 37° C.;-   6. Aspiration 20 to 30 times using a pipette, undigested pituitary    fragments being allowed to settle for 3 to 5 minutes;-   7. Aspiration of the suspended cells followed by centrifugation at    1200×g for 5 minutes;-   8. Re-suspension of the cells in culture medium of DM containing    0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1% non    essential amino acids, 1% glutamine and 0.1% gentamycin;-   9. Treatment of the undigested pituitary fragments 3 times with 30    ml aliquots of the collagenase and hyaluronidase;-   10. Pooling of the cell suspensions and dilution to a concentration    of 3×10⁵ cells/ml;-   11. Placing of 1.0 ml of this suspension in each of a 24 well tray,    with the cells being maintained in a humidified 5% CO₂/95% air    atmosphere at 37° C. for 3 to 4 days    Testing of Compounds

The test compound is dissolved in DMSO to a final concentration of 0.5%in the incubation medium.

1.5 hours prior to the assay, the cells are washed three times with DMEMcontaining 0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1%non essential amino acids (100×), 1% glutamine (100×), 1%penicillin/streptomycin (10,000 units of each per ml) and 25 mM HEPES atpH 7.4. Immediately prior to the assay, the cells are again washed twicein this medium.

Following this, 1 ml of fresh medium containing the test compound and 2nM GnRH is added to two wells. For other test compounds (where it isdesired to test more than one compound), these are added to otherrespective duplicate wells. Incubation is then carried out at 37° C. forthree hours.

Following incubation, each well is analysed by removing the medium fromthe well and centrifuging the medium at 2000×g for 15 minutes to removeany cellular material. The supernatant is removed and assayed for LHcontent using a double antibody radio-immuno assay. Comparison with asuitable control (no test compound) is used to determine whether thetest compound reduces LH release. Compounds according to the presentinvention have activity at a concentration from 1 nM to 5 μM.

1. A compound of Formula (I),

wherein A represents a direct bond or optionally substitutedC₁₋₅alkylene; R¹ represents hydrogen; optionally substituted C₁₋₈alkyl;or (CH₂)_(b)—R^(a), wherein R^(a) represents C₃₋₈cycloalkyl and b iszero or an integer from 1 to 6; R² represents an optionally substitutedmono- or bi-cyclic aromatic ring structure wherein the optionalsubstituents are selected from cyano, NR³R^(3a), optionally substitutedC₁₋₈alkyl, optionally substituted C₁₋₈alkoxy or halo; R³ and R^(3a) areindependently selected from hydrogen; optionally substituted C₁₋₈alkyland optionally substituted aryl; R⁴ is selected from an optionallysubstituted 3- to 8-membered heterocyclic ring containing from 1 to 4heteroatoms independently selected from O, N and S; or a group offormula III-a; III-b; III-c; III-d; III-e; III-f, III-g, III-h, III-i,III-j or III-k;

wherein het represents an optionally substituted 3- to 8-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from O, N and S; R⁶ and R^(6a), are selected from: (i) R⁶ andR^(6a) are independently selected from hydrogen and optionallysubstituted C₁₋₈alkyl; or (ii) R⁶ and R^(6a) together representcarbonyl; or (iii)

 represents an optionally substituted 3- to 8-membered heterocyclic ringcontaining from 1 to 3 further heteroatoms independently selected fromO, N and S, and R^(6a) represents hydrogen and optionally substitutedC₁₋₈alkyl; R⁷ represents hydrogen or optionally substituted C₁₋₈alkyl;R⁸are selected from: C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl andheterocyclyl wherein R⁸ is optionally substituted with halo, hydroxy,amino, NO₂, cyano, C₁₋₄alkanoyloxy, N—C₁₋₄alkylamino,N,N-di-C₁₋₄alkylamino, HO—C₂₋₄alkyl-NH—, HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-,—S(O_(n))—C₁₋₄alkyl, —N(R)S(O_(n))—C₁₋₄alkyl, —S(O_(n))N(R)—C₁₋₄alkyl orheterocyclyl optionally substituted by C₁₋₄alkyl, C₂₋₄alkenyl orC₂₋₄alkynyl, wherein R is hydrogen or C₁₋₄alkyl; R⁹ selected from: (i)R⁹ represents hydrogen, aryl, a 3- to 10 membered heterocyclic ring oroptionally-substituted C₁₋₈alkyl; and (ii) the structure N(R⁹R¹⁰)represents an optionally-substituted 3- to 10 membered heterocyclic ringoptionally containing from 1 to 3 further heteroatoms independentlyselected from O, N and S; R¹⁰ meets the definition in option (ii) for R⁹above or when R⁹ meets the definition in option (i) above R¹⁰ representshydrogen or optionally substituted C₁₋₈alkyl; R¹² and R^(12a) areselected from: (i) R¹² and R^(12a) are independently selected fromhydrogen or optionally substituted C₁₋₈alkyl; or (ii) R¹² and R^(12a)together with the carbon to which they are attached form an optionallysubstituted 3 to 7-membered cycloalkyl ring; R¹³ and R¹⁴ are selectedfrom: (i) R¹³ is selected from hydrogen; optionally substitutedC₁₋₈alkyl; optionally substituted aryl; —R^(d)—Ar, where R^(d)represents C₁₋₈alkylene and Ar represents optionally substituted aryl;and optionally substituted 3- to 8-membered heterocyclic ring optionallycontaining from 1 to 3 further heteroatoms independently selected fromO, N and S; and R¹⁴ is selected from hydrogen; optionally substitutedC₁₋₈alkyl and optionally substituted aryl; (ii) wherein R⁴ represents agroup of formula III-a, III-b or III-i, then the group NR¹³(—R¹⁴)represents an optionally substituted 3- to 8-membered heterocyclic ringoptionally containing from 1 to 3 further heteroatoms independentlyselected from O, N and S; or (iii) wherein R⁴ represents structureIII-e,

 represents an optionally substituted 3- to 8-membered heterocyclic ringoptionally containing from 1 to 4 heteroatoms independently selectedfrom O, N and S; n is 0 to 2; or a salt, pro-drug or solvate thereof. 2.A compound according to claim 1 wherein R⁹ represents hydrogen,optionally substituted aryl, an optionally substituted 3- to 10 memberedheterocyclic ring or optionally-substituted C₁₋₈alkyl and R¹⁰ representshydrogen or optionally substituted C₁₋₈alkyl wherein the optionalsubstituents on aryl, the heterocyclic ring and C₁₋₆alkyl are selectedfrom: hydroxy, amino, nitro, cyano, optionally-substituted aryl,optionally substituted 3- to 8-membered heterocyclyl containing from 1to 4 heteroatoms independently selected from O, N and S, —O—R^(b),C(O)NR^(b)R^(c), —NR^(b)R^(c), —NR^(c)C(O)—NR^(b)R^(c),—NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b), wherein R^(b) and R^(c) are as inclaim
 1. 3. A compound according to claim 2 wherein R⁹ is a C₁₋₆alkylgroup substituted by pyridyl, thienyl, piperidinyl, imidazolyl,triazolyl, thiazolyl, pyrrolidinyl, piperazinyl, morpholinyl,imidazolinyl, benztriazolyl, benzimidazolyl, pyrimidinyl, pyrazinyl,pyridazinyl, oxazolyl, furanyl, pyrrolyl, 1,3-dioxolanyl or 2-azetinyl,each of which is optionally substituted.
 4. A compound according toclaim 1 wherein the structure N(R⁹R¹⁰) represents anoptionally-substituted 3- to 10 membered heterocyclic ring optionallycontaining from 1 to 3 further heteroatoms independently selected fromO, N and S.
 5. A compound according to claim 4 wherein the 3- to 10membered heterocyclic ring is optionally substituted by one of moregroups selected from R¹⁵ wherein R¹⁵ is selected from optionallysubstituted aryl, an optionally substituted 3- to 10 memberedheterocyclic ring or optionally substituted C₁₋₄alkyl wherein theoptional substituents on aryl, a heterocyclic ring or C₁₋₆alkyl areselected from: hydroxy, amino, nitro, cyano, optionally-substitutedaryl, optionally substituted 3- to 8-membered heterocyclyl containingfrom 1 to 4 heteroatoms independently selected from O, N and S, and—O—R^(b), C(O)NR^(b)R^(c), —NR^(b)R^(c), —NR^(c)C(O)—R^(b),—C(O)NR^(b)R^(c), —NR^(c)S(O₀₋₂)R^(b), —S(O₀₋₂)R^(b), wherein R^(b) andR^(c) are as defined in claim
 1. 6. A compound according to claim 1wherein R⁴ is selected from a group of formula III-a, III-g, III-h,III-i, III-j or III-k:


7. A compound according to claim 1 wherein X and R⁸ represent either:—(a) X represents N and R⁸ represents cyano or —C(O)O—R^(b); or (b) Xrepresents N and R⁸ represents hydrogen.
 8. A compound according toclaim 1 wherein R² is selected from an optionally substituted monocyclicaromatic ring structure wherein the optional substituents are selectedfrom cyano, NR^(e)R^(f), optionally substituted C₁₋₈alkyl, optionallysubstituted C₁₋₈alkoxy or halo wherein R^(e) and R^(f) are independentlyselected from hydrogen, C₁₋₆alky or aryl.
 9. A compound according toclaim 1 wherein R¹ hydrogen.
 10. A compound selected from: isopropyl[(1E)-({(2S)-2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]carbamate; isopropyl[(1E)-({(2S)-2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]carbamate; and2-[({[(1E)-({(2S)-2-[5-[2-(2-azabicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}amino)(3-pyridin-4-ylpyrrolidin-1-yl)methylene]amino}carbonyl)oxy]-2-methylpropylacetate or a salt, pro-drug or solvate thereof.
 11. A pharmaceuticalformulation comprising a compound, or salt, pro-drug or solvate thereof,according to claim 1 and a pharmaceutically acceptable diluent orcarrier.